采用分子动力学模拟研究张力对β1整合素与ICAP1互作的影响  

Effects of Tension onβ1 Integrin and ICAP1 Interaction Using Molecular Dynamics Simulations

作　　者：石玉珍 方颖 吴建华 SHI Yuzhen;FANG Ying;WU Jianhua(Institute of Biomechanics,School of Bioscience and Bioengineering,South China University of Technology,Guangzhou 510006,China)

机构地区：[1]华南理工大学生物科学与工程学院,生物力学研究所,广州510006

出　　处：《医用生物力学》2024年第6期1197-1203,共7页Journal of Medical Biomechanics

基　　金：国家自然科学基金项目(12172137,12072117)。

摘　　要：目的探究张力调控ICAP1/β1整合素相互作用的机制与分子结构基础。方法基于ICAP1/β1整合素胞质尾部复合物的晶体结构数据(PDB ID:4DX9),通过拉伸分子动力学模拟,观察分析β1整合素上的张力加载对ICAP1/β1整合素复合物结构和结合力的影响。结果张力将通过诱导结合界面的局部变构来双向调节ICAP1/β1整合素复合物的解离,它将先提高后降低β1整合素对ICAP1的结合亲和力,阈值点发生在10 pN。对张力加载敏感的主要残基相互作用主要存在于ARG^(140)-THR^(789)、MET^(141)-THR^(789)和ASP^(145)-SER^(785)之中。结论随着加载在β1整合素胞质尾部的张力增加,结合面的变构将导致ICAP1对β1整合素活化的抑制作用先增强后减弱,张力转捩点出现在10 pN,提示力开启的整合素激活,需要具备足够的力学刺激强度。研究结果为靶向β1整合素的抗体药物研发提供了一条新思路。Objective To investigate the mechanism and molecular structural basis of the tension-regulated interaction between ICAP1 andβ1 integrin.Methods Based on the crystal structure data of the ICAP1/β1 integrin cytoplasmic tail complex(PDB ID:4DX9),tensile molecular dynamics simulations were conducted to observe and analyze the effects of tension loading onβ1 integrin on the structure and binding affinity of the ICAP1/β1 integrin complex.Results The tension modulated the dissociation of the ICAP1/β1 integrin complex bidirectionally by inducing local conformational variations at the binding interface.It initially increased and then decreased the binding affinity ofβ1 integrin for ICAP1.The threshold point occurred at 10 pN.The main tensionsensitive residue interactions were primarily located among ARG^(140)-THR^(789),MET^(141)-THR^(789),and ASP^(145)-SER^(785).Conclusions As the tension applied to the cytoplasmic tail ofβ1 integrin increased,the conformational variations at the binding interface resulted in an initial enhancement followed by a reduction in the inhibitory effect of ICAP1 onβ1 integrin activation.A tension threshold of 10 pN was observed.This indicated that force-induced integrin activation requires sufficient mechanical stimulus strength.This study has provided a new approach for the development of antibody drugs targetingβ1 integrins.

关 键 词：Β1整合素 整合素细胞质结构域相关蛋白-1 分子动力学模拟 力信号转导 

分 类 号：R318.01[医药卫生—生物医学工程]